While anti-inflammatory agents and hyaluronic acid-base viscous replacements have been developed to treat people with osteoarthritis, there has been little impact on the progression and treatment of the disease. What is more, there are few therapeutic strategies that aim to interact with the existing extracellular matrix (ECM) to stem disease progression and potentially provide an environment conducive to autologous repair. Osteoarthritis is a debilitating disease that, according to the Arthritis Foundation, affects over 7 million Americans. The disease is characterized by a breakdown of articular cartilage; including ECM molecules type II collagen, aggrecan, and hyaluronic acid (HA). Osteoarthritis is often triggered by injury, resulting in release of catabolic cytokines (e.g. IL-1?) and enzymatic (e.g. aggrecanase, hyaluronidase, and matrix metalloproteinase (MMP)) expression by chondrocytes. Aggrecanases initially degrade the aggrecan core protein. Once aggrecan is degraded, both HA and type II collagen are exposed and become susceptible to hyaluronidases and MMPs, respectively. Hyaluronidase cleaves HA, producing HA oligosaccharides that trigger additional MMP synthesis. The MMPs, specifically MMP3 and MMP13, degrade type II collagen. Like HA oligosaccharides, type II collagen fragments further stimulate cartilage catabolism through induction of cytokines and MMPs. Importantly, therapies that protect the ECM from degradation may halt this viscous cycle that perpetuates cartilage breakdown. Recently, we reported on a new class of biosynthetic molecules, coined peptidoglycans that mimic many of the functions of proteoglycans. The peptidoglycans can be designed to limit hyaluronidase degradation of HA and MMP degradation of collagen. Unlike the native proteoglycans, peptidoglycans are not susceptible to proteases because peptidoglycans do not contain the proteoglycan core protein. The peptidoglycans instead contain small peptides that simulate the desired core protein activity. Given the need to prevent ECM degradation to limit OA progression coupled with the preliminary evidence of the abilities of peptiodglycans, we hypothesize that proteoglycan mimics can protect HA and type II collagen in articular cartilage from cytokine-induced enzymatic degradation, thus suppressing cartilage erosion associated with OA. We further hypothesize, that lubricin mimics that interact with both HA and type II collagen can be used to restore the low friction properties of articular cartilage, thus protect th surface from mechanical wear. Our immediate goals are to optimize the peptidoglycans ex vivo, improve our mechanistic understanding of their function, and assess in vivo efficacy of the compounds. Our long term goals include formulating the peptidoglycans for delivery to injured joints to alleviate OA symptoms and protect against further ECM degradation.